4,10-Dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylic acids, salts and esters

ABSTRACT

The present invention relates to 4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylic acids, salts and esters having the formula: ##STR1## wherein R 1  is hydrogen, lower alkyl, halogen, hydroxy or lower alkoxy; R 2  is hydrogen, aralkyl or lower alkyl; R 3  is hydrogen or lower alkyl and their pharmaceutically acceptable salts. 
     These compounds are indicated in the management of allergic conditions such as bronchial asthma, hay fever and the like.

The present invention relates to4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylicacids, salts and esters having the formula: ##STR2## wherein R₁ ishydrogen, lower alkyl, halogen, hydroxy or lower alkoxy; R₂ is hydrogen,aralkyl or lower alkyl; R₃ is hydrogen or lower alkyl and theirpharmaceutically acceptable salts.

In the above definitions for R₁, R₂ and R₃, lower alkyl and the loweralkyl portion of lower alkoxy and aralkyl is meant to have 1-6 carbonatoms such as, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, and so on. The aryl portion of aralkyl is meant to be anaromatic hydrocarbon radical, typically of 6-10 carbon atoms such asphenyl, tolyl and so on.

The compounds of the present invention, including their salts, have beenfound to inhibit and prevent allergic and asthmatic reactions. Forexample, at a dose of 0.5 to 100 mg/kg intravenously, Compounds I ortheir salts were found to prevent allergic and asthmatic reactions inthe passive cutaneous anaphylaxis (PCA) screen. This PCA screen is amodification of procedures described by I. Mota, Life Sciences, 7: 465(1963) and Z. Ovary and O. Bier, Proc. Soc. Exptl. Biol. Med., 81: 585(1952). The compound8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylicacid is particularly preferred because at a dose of 0.5 mg/kg, the PCAscreen shows a 46% inhibition of the allergic reactions.

In view of the above biological activity, the compounds of thisinvention, including their salts, are indicated in the management ofpatients with allergic manifestations such as bronchial asthma and hayfever. Generally speaking, a dose of 0.5 mg/kg to 100 mg/kg orally,parenterally or by inhalation one to three times daily is suggested. Aswith any anti-allergic therapy, the dosage regimen must be titrated toindividual needs by methods well-known to the healing arts.

In order to use these compounds and their salts, they are to beformulated into conventional dosage forms such as tablets, elixers andaerosols by known pharmaceutical technology. For example, tablets can beprepared by selecting the active ingredient, mixing with lactose andcompressed into tablets with suitable tabletting excipients known in theart.

The above Compound I is prepared in accordance with the followingreaction scheme: ##STR3##

Referring to the above reaction scheme, Compound II is treated withCompound III at an elevated temperature, such as about 120° C., under anatmosphere of nitrogen. Compound IV is then treated with diphenyl etherwhich results in the production of Compound V. In turn, Compound V istreated with R₂ iodide in the presence of potassium carbonate anddimethyl formamide under an atmosphere of nitrogen to yield Compound VI.Hydrolysis of Compound VI results in those compounds of the invention inwhich R₂ is other than hydrogen.

Similarly, hydrolysis of Compound V leads directly to those compounds ofthe invention in which R₂ and R₃ are hydrogen.

Salts of the carboxylic acids of the present invention are produced bytreating the acid with bases such as sodium carbonate, potassiumcarbonate, calcium carbonate and so on, and recovering the salt byconventional procedures.

Salts of the basic compounds of this invention are prepared by treatingthe parent base with an acid, for example a mineral acid, such ashydrochloric, sulfuric, nitric and phosphoric in stoichiometric amountsand recovering the salts produced by conventional procedures.

The starting materials were prepared as follows:

3-Aminochromone by the method of G. J. P. Beckett and G. P. Ellis,Tetrahedron Letters, 719 (1976); 3-nitro-7-methoxy-4H-1-benzopyran-4-oneby the method described in our copending application Ser. No. 710,996filed Aug. 2, 1976; 3-nitro-6-chloro-4H-1-benzopyran-4-one by the methodof M. von Strandtmann and S. Klutchko, U.S. Pat. No. 3,906,005. Diethylethoxymethylenemalonate is available from Aldrich Chemical Company.

The aforesaid disclosures are incorporated by reference herein.

To further illustrate the practice of this invention, the followingexamples are included. The temperatures hereinafter are in degreesCentigrade.

EXAMPLE 1 ##STR4## 3-Amino-6-chloro-4H-1-benzopyran-4-one

Sodium dithionite (20 g, 0.115 mole) was added to a suspension of3-nitro-6-chloro-4H-1-benzopyran-4-one (7.0 g, 0.037 mole) in water (80ml) and absolute ethanol (30 ml). The reaction mixture was refluxedunder nitrogen for 3 hrs., concentrated at reduced pressure andfiltered. The solids were washed with water and recrystallized fromacetone to give yellow crystals (5.44 g, 90%), m.p. 184°-186°.

Anal. Calcd. for C₉ H₆ ClNO₂ : C, 55.10; H, 3.06; N, 7.15; Cl, 18.10.Found: C, 55.01; H, 3.14; N, 6.62; Cl, 18.11.

EXAMPLE 2 ##STR5## 3-Amino-7-methoxy-4H-1-benzopyran-4-one

Sodium dithionite (140 g, 0.804 mole) was added to a suspension of3-nitro-7-methoxy-4H-1-benzopyran-4-one (50 g, 0.261 mole) in water (330ml) and absolute ethanol (110 ml). The reaction mixture was stirred for15 min., concentrated at reduced pressure and filtered. The solids werewashed with water and recrystallized from ethyl acetate to give lightbrown crystals, 159°-162°.

Mass Spectrum: Observed molecular ion, 191.0645; Calculated for C₁₀ H₉NO₃, 191.0582.

EXAMPLE 3 ##STR6## Diethyl{[(6-chloro-4-oxo-4H-1-benzopyran-3-yl)amino]methylene}propanedioate

A mixture of 3-amino-6-chlorochromone (1.95 g, 0.01 mole) and diethylethoxymethylenemalonate (3.5 g, 0.016 mole) was heated under nitrogen at120° for 4 hrs. The reaction mixture was cooled. The product, whichprecipitated, was filtered off and washed with ethyl acetate.Recrystallization from ethyl acetate gave white crystals (2.51 g, 68%),m.p. 143°-145°.

Anal. Calcd. for C₁₇ H₁₆ ClNO₆ : C, 55.82; H, 4.41; N, 3.83; Cl, 9.69.Found: C, 55.86; H, 4.50; N, 3.88; Cl, 9.60.

NMR (CDCL₃) δ 10.70 (d, l, N-H (J = 14Hz) exchanges with D₂ O), 8.5-7.4(m, 4, ArH), 4.7-4.0 (m, 4, CH₂) and 1.6-1.2 (m, 6, CH₃).

IR 3300-3200 (N-H), 1680 (CO) and 1650 (CO).

UV 217 (23,000), 292 (23,000), 323 (26,000).

EXAMPLE 4 ##STR7## Diethyl{[(4-oxo-4H-1-benzopyran-3-yl)amino]methylene}propanedioate

A mixture of 3-aminochromone (8.0 g, 0.05 mole) and diethylethoxymethylenemalonate (17.3 g, 0.08 mole) was heated under nitrogen at140° C. for 2.5 hrs. The reaction mixture was cooled. The product, whichcrystallized out was filtered off and triturated with petroleum ether.Recrystallization from ethyl acetate - absolute ethanol gave whitecrystals (10.3 g, 62.5%), m.p. 155°-157° C.

Anal. Calcd. for C₁₇ H₁₇ NO₆ : C, 61.63; H, 5.17; N, 4.23. Found: C,61.64; H, 5.27; N, 4.43.

NMR (CDCl₃) δ 10.70 (d, l, NH, J = 14 Hz, exchanges with D₂ O), 8.30 (d,l, CH, J = 14Hz, collapses to singlet with D₂ O), 8.11 (s, l, C₂ H),7.55 (m, 4, ArH), 4.35 (q, 2, CH₂, J = 7Hz), 4.28 (q, 2, CH₂, J = 7Hz),1.49 (t, 3, CH₃, J = 7Hz), 1.32 (t, 3, CH₃, J = 7Hz).

IR 3095 (NH), 1675 (CO), 1642 (CO).

UV 218 (23,000), 284 (20,400), 320 (28,000).

EXAMPLE 5 ##STR8## Diethyl{[(7-methoxy-4-oxo-4H-1-benzopyran-3-yl)amino]methylene}propanedioate.

Prepared by the procedure described for Example 4 from crude3-amino-7-methoxy-4-H-1-benzopyran-4-one (35 g). Recrystallization fromethyl acetate gave pale yellow crystals (22.5 g, 34%), m.p. 139°-141° C.

Anal. Calcd. for C₁₈ H₁₉ NO₇ : C, 59.83; H, 5.30; N, 3.88. Found: C,59.81; H, 5.15; N, 3.75.

NMR (CDCl₃) δ 10.70 (d, l, NH, exchanges with D₂ O, J = 14Hz), 8.30 (d,l, CH, collapses to singlet with D₂ O, J = 14Hz), 8.03 (s, l, C₂ H),8.19 (d, l, C₅ H), 7.0 (m, 2, C₆ H and C₈ H), 4.32 (m, 4, 2CH₂), 3.95(s, 3, OCH₃) and 1.40 (m, 6, 2CH₃).

IR 3100 (NH), 1685 (CO), 1652 (CO), 1620 (CO).

UV 230 (20,500), 299 (32,450).

EXAMPLE 6 ##STR9## Ethyl8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate

Diethyl{[(6-chloro-4-oxo-4H-1-benzopyran-3-yl)amino]methylene}propanedioate(5.0 g, 0.0137 mole) was added to diphenyl ether (30 ml) at 200°. Thereaction mixture was refluxed (bath temp. 280°-290° ) for 60 min. Theproduct, which crystallized out on cooling, was filtered off and washedwith ether. Recrystallization from DMF gave white crystals (4.05 g,93%), m.p. 330°-338° (dec).

Anal. Calcd. for C₁₅ H₁₀ ClNO₅ : C, 56,35; H, 3.15; N, 4,38; Cl, 11.09.Found: C, 56.35; H, 3.23; N, 4.34; Cl, 11.17.

NMR (TFA) δ 9.41 (s, l, C₂ H), 8.50 to 7.90 (m, 3, ArH), 4.78 (q, 2,CH₂), 1.61 (t, 3, CH₃).

IR 3300-3000 (NH), 1730 (CO), 1680 (CO).

UV 247 (24,000), 262 (27,000), 354 (7,200).

EXAMPLE 7 ##STR10## Ethyl4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate

Prepared by the method described for Example 6 from diethyl{[(4-oxo-4H-1-benzopyran-3-yl)amino]methylene}propanediaote (3.18 g,0.096 mole). Recrystallization from DMF gave off-white crystals (1.65 g,52%), m.p. 294°-295° C.

Anal. Calcd. for C₁₅ H₁₁ NO₅ : C, 63.16; H, 3.89; N, 4.91. Found: C,63.09; H, 3.91; N, 4.94.

NMR (TFA) δ 9.41 (s, l, C₂ H), 8.52 (m.d., 1, ArH), 8.02 (m, 3ArH), 4.80(q, 2, CH₂, J = 7Hz), 1.62 (t, 3, CH₃, J = 7Hz).

IR 3160 (NH), 3080 (NH), 1730 (CO), 1675 (CO), 1632 (CO).

UV 242 (22,100), 257 (22,400), 347 (7,400).

EXAMPLE 8 ##STR11## Ethyl7-methoxy-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2b-]pyridine-3-carboxylate

Prepared by the method described for Example 6 from diethyl{[(7-methoxy-4-oxo-4H-1-benzopyran-3-yl)amino]methylene}propanedioate(20.0 g, 0.0555 mole). Recrystallization from DMF gave white crystals(11.3 g, 64.5%), m.p. 277°-280° C.

Anal. Calcd. for C₁₆ H₁₃ NO₆ : C, 60.95; H, 4.16; N, 4.44. Found: C,60.80; H, 4.34; N, 4.68.

EXAMPLE 9 ##STR12## Ethyl1-methyl-8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate

A mixture of ethyl8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate(0.5 g, 0.0016 mole), methyl iodide (0.5 g, 0.0035 mole) and potassiumcarbonate (0.23 g, 0.0017 mole) in dimethyl formamide (25 ml) wasstirred at 100° for 3 hrs. under nitrogen. The reaction mixture wascooled. The product, which precipitated, was filtered, washed with waterand dried. Recrystallization from DMF gave white crystals (0.47 g, 90%),m.p. 295°-297°.

Anal. Calcd. for C₁₆ H₁₂ ClNO₅ : C, 57.59; H, 3.62; N, 4.20; Cl, 10.62.Found: C, 57.43; H, 3.68; N, 4.15; Cl, 10.69.

NMR (TFA) δ 9.25 (s, l, C₂ H), 8.60 to 7.80 (m, 3, ArH), 4.92 (s, 3, CH₃N), 4.80 (q, 2, C₂), 1.62 (t, 3, CH₃).

IR 1685 (CO), 1645 (CO).

UV 240 (24,000), 252 (26,000), 264 (24,000), 295 (9,500), 345 (8,500),356 (8,500).

EXAMPLE 10 ##STR13## Ethyl1-methyl-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate

Prepared by the method described for Example 9 from ethyl4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate(8.0 g, 0.028 mole). Recrystallization from DMF gave off-white crystals(8.25 g, 98.5%), m.p. 251°-254° C.

Anal. Calcd. for C₁₆ H₁₃ NO₅ : C, 64.21; H, 4.38; N, 4.68. Found: C,64.22; H, 4.39; N, 4.69.

NMR (TFA) δ 9.28 (s, l, C₂ H), 8.53 & 8.01 (d & m, 4, ArH), 4.99 (s, 3,CH₃ N), 4.83 (q, 2, CH₂, J = 7Hz), 1.68 (t, 3, CH₃, J = 7Hz).

IR 1683 (CO), 1645 (CO).

UV 247 (24,100), 338 (8,500).

EXAMPLE 11 ##STR14## Ethyl1-ethyl-8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate

Prepared from ethyl8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate(3.19 g, 0.01 mole) and ethyl iodide (6.24 g, 0.04 mole) by the methoddescribed for Example 9. Recrystallization from DMF gave white crystals(2.7 g, 78%), m.p. 257°-259°.

Anal. Calcd. for C₁₇ H₁₄ ClNO₅ : C, 58.72; H, 4.06; N, 4.03; Cl, 10.20.Found: C, 58.56; H, 4.01; N, 4.07; Cl, 10.26.

NMR (TFA) δ 9.28 (s, l, C₂ H), 8.60 to 7.80 (m, 3, ArH), 5.45 (q, 2, CH₂--N), 4.83 (q, 2, CH₂ --O), 1.82 (t, 3, CH₃) and 1.68 (t, 3, CH₃).

IR 1685 (CO), 1650 (CO).

UV 240 (24,000), 252 (27,000), 263 (25,000), 295 (9,500), 347 (9,000),363 (9,000).

EXAMPLE 12 ##STR15## Ethyl1-butyl-8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate

Prepared from ethyl8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate(3.195 g, 0.01 mole) and butyl iodide (7.36 g, 0.04 mole) by the methoddescribed for Example 9. Recrystallization from methanol gave whitecrystals (3.575 g, 95%), m.p. 226°-228°.

Anal. Calcd. for C₁₉ H₁₈ ClNO₅ : C, 60.73; H, 4.83; N, 3.73; Cl, 9.43.Found: C, 60.74; H, 4.68; N, 3.72; Cl, 9.60.

NMR (TFA) δ 9.28 (s, l, C₂ H), 8.60 to 7.80 (m, 3ArH), 5.40 (t, 2, CH₂--N), 4.85 (q, 2, CH₂ --O) and 2.50 to 1.00 (m, 10 aliphatic).

IR 1685 (CO), 1645 (CO).

UV 240 (24,000), 252 (27,000), 263 (25,000), 295 (9,500), 347 (9,000),363 (9,000).

EXAMPLE 13 ##STR16##8-Chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylicacid

A suspension of ethyl8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate(3.0 g, 0.0094 mole) in 6N hydrochloric acid (100 ml ) was refluxedunder nitrogen for 15 hrs., cooled and filtered. The residue was washedwith water and with acetone. Recrystallization from DMF gave whitecrystals (2.4 g, 87%), m.p. 325°-327°.

Anal. Calcd. for C₁₃ H₆ NO₅ Cl: C, 53.54; H, 2.07; N, 4.80; Cl, 12.16.Found: C, 53.25; H, 2.18; N, 4.81; Cl, 12.29.

NMR (TFA) δ 9.33 (s, l, C₂ H), 8.60 to 7.60 (m, 3, ArH).

IR 3250 (NH), 2800-2500 (OH), 1745 (CO), 1675 (CO), 1630 (CO).

UV 257 (30,000), 352 (7,200).

EXAMPLE 14 ##STR17##4,10-Dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylicacid

Prepared by the method described for Example 13 from ethyl4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate(5.0 g, 0.0175 mole). Recrystallization from DMF gave white crsytals(4.13 g, 94%), m.p. dec > 330° C.

Anal. Calcd. for C₁₃ H₇ NO₅ : C, 60.71; H, 2.74; N, 5.45. Found: C,60.61; H, 2.94; N, 5.73.

NMR (TFA) δ 9.35 (s, l, C₂ H), 8.7-7.6 (m, 4, ArH).

IR 3180 (NH), 3050 (COOH), 2800-2300 (COOH), 1730 (CO), 1670 (CO), 1625(CO).

UV 244 (shoulder) (24,400), 252 (27,160), 336 (shoulder) (6,840), 346(7,120).

EXAMPLE 15 ##STR18##7-Methoxy-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylicacid

Prepared by the procedure described for Example 13 from ethyl7-methoxy-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate(850 mg). Recrystallization from DMF gave white crystals (640 mg,82.5%), m.p. 318°-319° C.

Anal. Calcd. for C₁₄ H₉ NO₆ : C, 58.54; H, 3.16; N, 4.88. Found: C,58.35; H, 3.27; N, 4.86.

EXAMPLE 16 ##STR19##1-Methyl-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylicacid

Prepared by the method described for Example 13 from ethyl1-methyl-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate(6.0 g, 0.02 mole). Recrystallization from DMF gave pinkish whitecrystals (4.8 g, 87.5%), m.p. 308°-312°.

Anal. Calcd. for C₁₄ H₉ NO₅ : C, 61.99; H, 3.34; N, 5.16. Found: C,61.84; H, 3.41; N, 5.12.

NMR (TFA) δ 9.19 (s, l, C₂ H), 8.48 (d, l, ArH), 7.96 (m, 3, ArH), 4.92(s, 3, CH₃).

IR 2600 (COOH) broad, 1730 (CO), 1675 (CO), 1629 (CO).

UV 207 (21,000), 251 (27,300), 352 (8,000).

EXAMPLE 17 ##STR20##1-Methyl-8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylicacid

Prepared by the method described for Example 13 from ethyl1-methyl-8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3carboxylate(3.0 g, 0.009 mole). Recrystallization from DMF gave white crystals(2.35 g, 86%), m.p. 295°-297°.

Anal. Calcd. for C₁₄ H₈ ClNO₅ : C, 55.01; H, 2.64; N, 4.58; Cl, 11.60.Found: C, 55.20; H, 2.81; N, 4.64; Cl, 11.62.

NMR (TFA) δ 9.17 (s, l, C₂ H), 8.60 to 7.80 (m, 3, ArH), 4.83 (s, 3,CH₃).

IR 3070 (OH), 2800-2500 (OH), 1735 (CO), 1665 (CO).

UV 258 (28,500), 342 (8,000), 357 (8,000).

EXAMPLE 18 ##STR21##1-Ethyl-8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylicacid

Prepared by the method described for Example 13 from ethyl1-ethyl-8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate(3.47 g, 0.01 mole). Recrystallization from DMF gave white crystals(2.97 g, 93%), m.p. 295°°-300° (dec).

Anal. Calcd. for C₁₅ H₁₀ ClNO₅ : C, 56.35; H, 3.15; N, 4.38; Cl, 11.09.Found: C, 56.09; H, 3.34; N, 4.71; C1, 11.07.

NMR (TFA) δ 9.17 (s, l, C₂ H), 8.60 to 7.80 (m, 3, ArH), 5.28 (q, 2,CH₂) and 1.75 (t, 3, CH₃).

IR 3070 (OH), 2800-2500 (OH), 1715 (CO), 1665 (CO).

UV 256 (28,500), 344 (8,000), 356 (8,000).

EXAMPLE 19 ##STR22##1-Butyl-8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylicacid

Prepared by the method described for Example 13 from ethyl1-butyl-8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate(3.40 g, 0.009 mole). Recrystallization from DMF gave white crystals(2.84 g, 90%), m.p. 271°-273°.

Anal. Calcd. for C₁₇ H₁₄ ClNO₅ : C, 58.72; H, 4.06; N, 4.03; Cl, 10.20.Found: C, 58.42; H, 4.01; N, 3.81; Cl, 10.35.

NMR (TFA) δ 9.17 (s, l, C₂ H), 8.60 to 7.80 (m, 3, ArH), 5.22 (t, 2, CH₂N) and 2.50 to 1.00 (m, 7 aliphatic).

IR 3060 (OH), 2800-2500 (OH), 1730 (CO), 1660 (CO).

UV 257 (29,000), 348 (8,000), 358 (8,000).

We claim:
 1. A compound of the formula: ##STR23## wherein R₁ ishydrogen, lower alkyl, halogen, hydroxy or lower alkoxy; R₂ is hydrogenphenyl lower alkyl or lower alkyl; R₃ is hydrogen or lower alkyl andtheir pharmaceutically acceptable salts.
 2. A compound according toclaim 1 which is ethyl8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate.3. A compound according to claim 1 which is ethyl4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate.4. A compound according to claim 1 which is ethyl7-methoxy-4,10-dihydro-4.10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate.5. A compound according to claim 1 which is ethyl1-methyl-8-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate.6. A compound according to claim 1 which is ethyl1-methyl-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate.7. A compound according to claim 1 which is ethyl1-ethyl-8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate.8. A compound according to claim 1 which is ethyl1-butyl-8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate.9. A compound according to claim 1 which is8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylicacid.
 10. A compound according to claim 1 which is4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylicacid.
 11. A compound according to claim 1 which is7-methoxy-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylicacid.
 12. A compound according to claim 1 which is1-methyl-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylicacid.
 13. A compound according to claim 1 which is1-methyl-8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylicacid.
 14. A compound according to claim 1 which is1-ethyl-8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylicacid.
 15. A compound according to claim 1 which is1-butyl-8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylicacid.